We showed previously than active immunotherapy allows for Tau clearance in the periphery and improves cognitive deficits promoted by Tau pathology in a well-defined mutant Tau mutant model [ 51].
To date, tau-targeted immunisation has been explored exclusively in different mutant tau mouse models because these mice develop NFTs in their brains [ 5].
Significantly, the expression of mutant tau in mouse models of Alzheimer's disease-like tau neuropathologies can result in a significant loss of dendritic spines and synapses (Mocanu et al., 2008; Bittner et al., 2010; Rocher et al., 2010).
This model expresses mutant tau protein and has been well studied for pathological and behavioural abnormalities (116); consequently, a simple battery of motor tests could be used to define the K3 phenotype.
In the triple transgenic mouse model of Alzheimer's disease and in a mouse model expressing human mutant tau on a null background for the E3 ubiquitin ligase parkin, stimulation of autophagy promoted the degradation of insoluble tau (Caccamo et al., 2011; Majumder et al., 2011; Rodriguez-Navarro et al., 2011).
However, it became increasingly obvious from animal models expressing mutant Tau that Tau pathology appears prominently in the stratum lucidum (s.l). of area CA3 where axons of granule cells form the mossy fiber path [ 7- 9].
Importantly, although it is true that levels of mutant tau overexpression are very high in this model, the pR5 mouse model of tauopathy in which levels of mutant tau expression are much lower, at ~70 % endogenous tau, also shows UPR activation [ 17, 18].
Similarly several studies have now demonstrated protective effects of microtubule stabilization or increased microtubule acetylation in other models involving axonal degeneration such as mutant tau induced axon degeneration [ 44- 46] and models of ALS [ 47].
In the current study, Wegmann et al (2015) made use of such models that express FTD mutant tau (P301L tau).
Recent data from the rTauEC transgenic mouse model in which human P301L mutant tau overexpression uniquely in the EC leads, at advanced age (24 months), to the appearance of numerous human tau containing NFT in synaptically connected brain regions suggests that tau spreading can occur by transfer of misfolded human tau protein between neurons [ 6, 10, 16].
